Substituted amino alkyl tetrazoles



Patented May 17, 1949 UNITED STATES 2,470,085 SUBSTITUTED AMINO ALKYLTETRAZOLES Edward Short Hills,

K. Harvill, Orange, and Robert M. Herbst, N. 3., assignors to E.Bilhuber, Inc.,

Orange, N. J a corporation of New Jersey No Drawing. Application March7, 1947, Serial No. 733,178

4 Claims.

1 This invention relates to new and valuable chemical compounds whichare substituted amino alkyl tetrazoles of the general formula:

wherein R1 may be hydrogen, alkyl, aryl, or aralkyl and wherein R3 andR4, either one or both, may be hydrogen, alkyl, alkenyl, cycloalkyl,aryl or aralkyl, or R3 and R4 may together with nitrogen form a cyclicsystem, for example, piperidine or morpholine, and wherein R2 may be anaryl, cycloalkyl, alkyl or heterocyclic group, such as pyridyl,quinolyl, isoquinolyl, etc.

This application is a continuation-in-part of our copending applicationsSerial No. 546,731, filed July 26, 1944:, and Serial No. 618,580, filedSeptember 25, 1945.

The new compounds aforesaid are valuable therapeutic agents, which areparticularly effective as sedatives and anesthetics, such action beingcompletely unexpected and never having been associated with themolecular configuration exhibited by these compounds.

These therapeutic agents are produced from hitherto unknownintermediates, substituted alpha-halogen alkyl tetrazoles, which are newcompounds especially valuable for the synthesis of therapeuticallyuseful tetrazoles. These substituted alpha-halogen alkyl tetrazoles havethe following general formula:

wherein R1 is hydrogen, alkyl, aryl or aralkyl, X is chlorine or bromineand R2 is an aryl, cycloalkyl, alkyl or heterocyclic group, such aspyridyl, quinolyl, isoquinolyl, etc.

These alpha-halogen alkyl tetrazoles are prepared as described in ourabove mentioned copending applications, from N-substituted amides ofalpha-halogen acids, by causing hydrazoic acid or sodium azide to reactwith the product formed by the interaction of phosphorus pentachlorideand the substituted amide.

The following example, taken from said copending applicationsillustrates the method as specifically applied to the synthesis of thealphahalogen alkyl tetrazole, l-phenyl-B-chloromethyl tetrazole.

EXAMPLE 56 grams of chloroacetanilide and 500 cc. of anhydrous benzenewere placed in a suitable reaction vessel, 72 grams of phosphorusPentachloride were added and the mixture was allowed to stand at roomtemperature until a clear solution formed. After removing the benzeneand phosphorus oxychloride, the residue was immediately treated with abenzene solution of 23 grams of hydrazoic acid. After the initialreaction had subsided, the solution was refluxed until the evolution ofhydrogen chloride had ceased. The benzene Was removed and the residuerefluxed with water. From the cooled solution, 58 grams (90.5% oftheory) of 1-phenyl-5-ch1oromethyl tetrazole was obtained as acolorless, crystalline material from carbon tetrachloride M. P. '76-'77"C.

Calculated N=28.86%, N=29.00%, C1=18.26%.

In similar fashion other intermediates may be prepared, as illustratedby the numerous exampics in each of said copending applications.

From these intermediate substituted alphahalogen alkyl tetrazoles, thedesired substituted amino alkyl tetrazoles are produced by reaction withprimary or secondary amines as shown in the following equation:

Cl=18.22%; found 29 grams of l-phenyl-S-chloromethyl tetrazole, 35 cc.of diethylamine and cc. of benzene were refluxed for 3.5 hours. Theresidue left Example 2 20 grams of 1-cyclohexyl-5-chloromethyltetrazole, 10.5 grams of sodium bicarbonate and 100 cc.- of allyl aminewere refluxed for 3.5 hours. Aqueous sodium hydroxide was added to theresidue le'ft after evaporation of the allyl amine.Thealkalinesolutionwas distilled to removeany unrea'cted amine and theloyclohexyl-5-allylaminomethyl 'tetrazole'separated as an oil that wastaken up in ether and'dried'over sodium'sul- :phate. The-eth-er"solution"was saturated with dry hydrogen chloride. The1-cyclohexyl-5- allylamirio methyl tetrazole hydrochloride precipitatedas'a white solid that was recrystallized from isopropyl alcohol. M. P.1755-176 C. Yield :grams.

Calculated, -N=27.19%; found, N=26.91%.

Example 3 19.4 grams of 1-phenyl-5-chl0romethyl tetrazole, 10.5 grams ofsodium bicarbonate, 50 cc. of aqueous 70% ethyl amine and 200 cc. of 99%isopropyl 'alcohol were refluxed for 4.5 hours. Theresidue'leftupon-evaporation of the solvent was madestrongly alkaline with aqueoussodium hydroxide. 'I-phenyl-S-ethyIamino methyl tetrazole separated asan oil which was taken up in ether and dried over sodium'sulphate. Theether solution was saturated with dry hydrogen chloride and thel-phenyl-fi-ethylamino methyl tetrazole hydrochloride separated as awhite solid which was recrystallized from aqueous isopropyl alcohol. M.P. 206-207 C. dec. Yield 19 grams.

Calculated, N=29.23%; found, N=29.22%.

In similar manner, the following compounds may be obtained:

1-phenyl-fi-morpholinomethyl tetrazole. M. P.

'96-97 C. 1-phenyl-5-piperidinomethyl tetrazole. M. P.

90.5-91.5 C. 1-isoamyl-fi-piperidinomethyl tetrazole hydrochloride. M.P. '166-166;5'C. 1-'cyclohexyl-5-cyclohexylaminomethyl tetrazole.

M.P. 83-8; C. 1-cyclohexyl-5-aminomethyl tetrazole hydrochloride. M. P.231 C."dec. '1-'cyclohexyl-S-dimethylaminomethyl tetrazole.

M. P. 60.5-61.0 C. 1-phenyl-5-isoamylaminomethyl tetrazolehydrochloride. M. P. 143-144 C. 1-p' methoxyphenyl-5-diethylaminomethyltetrazole hydrochloride. M. P. 1765-177" C. dec.l-m-nitrophenyl-5-diethylaminomethyl tetrazole. M. P. 96-97 C.1-phenyl-5-benzylaminomethyl tetrazole hydrochloride. 'M.P.217.5-218'.5C.dec.

and sterilizedby heating underpressuremately mixed wi tilled water.After '4 1-m-aminopheny1-E-diethylaminomethyl tetrazole. M. P. 71-725 C.1-phenyl-5-allylaminomethyl tetrazole hydrochloride. M. P. 189-190 C.dec. 1-phenyl-5-b-hydroxyethylaminomethyl tetrazole hydrochloride. M. P.150-151 C. dec. 1-phenyl-5-isobutylaminomethyl tetrazole hydrochloride.M. P. 167-168 C. 1-phenyl-5-ox-dibutylaminoethyl tetrazolehydrochloride. M. P. 142-143 C. dec. 1-cyclohexyl-5-N-methyl-N-b-phenylpropylaminom'ethyl tetrazole. M. P. -81 C.1-p-nitrophenyl-5-diethylaminomethyl tetrazole.

M. P. '72-'73 C. 1-cyclohexyl-5-N-allyl-N 2 heptylaminomethyl tetrazole.B. P. 191-193 C./3 mm. l ox-naphthyl-fi-diethylaminomethyl MIP. 68-69 C.1 cyelohexyl-5-N-methyl-N-2-(6-methyl-6- hy droxy heptyl) aminomethyltetrazole. M. P. 80-81 C. 1-phenyl-5-isopropylaminomethyl tetrazolehydrochloride. M. P. 151.5-152.5 C. dec.1-cyclohexyl-S-propyIaminomethyl tetrazole hydrochloride. M. P. 210 C.dec. l-phenyl-5-N-ethyl-N-phenylaminomethyl tetrazole. M. P. 72.5-73.5C. 1 phenyl 5 ox-ethyl-b-hydroxyethylaminomethyl tetrazole. M. P.117-118" C. -1'- phenyl 5-ox-methyl-b-hydroxyethylaminomethyl'tetrazole. M. P. -78.078;5 C. l-phenyl-5-ox-m'ethylamlnoethyltetrazole hydrochloride. M. P. 195-196 C. dec.1-methyl-5-diethylaminomethyl tetrazole. B. P.

134-136-C./2.5 mm. 1-phenyl-fi-ox-diethylaminoethyl tetrazolehydrochloride. M. P.1'56-157C.dec.

tetrazole.

1-phenyl-5-methylaminomethyl tetrazole hydrochloride. M. P. 227 C.-dec.1-p hydroxyphenyl-5-diethylaminomethyl tetrazole hydrochloride. M. P.165-166 -C. dec. l-b-naphthyl --5 diethylaminomethyl tetrazolehydrochloride. M. P. 151-152" C. -1-o-diphenyl-5 --diethylaminomethyltetrazole hydrochloride. M. P. 151-15-2-C.'1-benzyl=5-diethylaminomethyl tetrazole hydrochloride. M. P. 145-146"C. -1-(3'-phenan-thr-yl) -5-diethylaminomethyl tet razo'le. M.P.119.5-1-20'.5 C.

In the foregoin 'examples,details 'for' the preparation'of salt's'of'the new compounds'have been disclosed. By virtue of their solubility inwater, these salts are particularly useful in the 'f'o'rmulation ofmedicinal agents containing salts of these new tetrazole-compounds asactive therapeutic agents of thecharacter above stated.

aminomethyl tetrazole hydrochloride is dissolved in sufiicient distilledwater to :make the volume of the resulting solution exactly2000 ml..This provides a'10% solution of 1-phenyl-5-diethylaminomethyl tetrazolehydrochloride which may be used orally-or whichmay'be placed in ampulesminutes foruparenteral administration. 5 Ex l 5 Four hundred grams ofl-phenyl o-diethylaminomethyl tetragole hydrochloride is jinti.

5 q grams ofpotatmst and granulatedjwr I ng the granulation may bepressed into tablets ofsuitable size andshape and grams of L fortherapeutic use, for example, to contain 100 mgm. of the salt (which isequivalent to approxi mately 85 mgm. of the active basic component).

Example 6 Two hundred grams of 1-alpha-naphthyl-5- diethylaminomethyltetrazole hydrochloride is dissolved in sufficient distilled Water tomake the volume of the resulting solution exactly 2000 ml. This providesa solution of l-alpha-naphthyl--diethylaminomethy1 tetrazolehydrochloride which may be used orally or which may be placed in ampulesand sterilized by heating under pressure for 30 minutes for parenteraladministration.

Example 7 Four hundred grams of l-alpha-naphthyl-5- diethylaminomethyltetrazole hydrochloride is intimately mixed with 500 grams of potatostarch and 100 grams of talc, and granulated with distilled water. Afterdrying, the granulation may be pressed into tablets of suitable size andshape for therapeutic use, for example, to contain 100 mgm. of the salt.

Example 8 tilled water. After drying, the granulation may be pressedinto tablets of suitable size and shape for therapeutic use, forexample, to contain mgm. of the salt.

We claim:

1. Substituted amino alkyl tetrazoles having the general formula:

wherein R1 is selected from the group consisting of hydrogen, alkyl,aryl and aralkyl; R2 is selected from the group consisting of alkyl,aryl, aralkyl and cycloalkyl; and wherein the is selected from among thefollowing: (1) a radical wherein R3 and R4 are Selected from the groupConsisting of hydrogen, alkyl, alkenyl, cycloalkyl, aryl and aralkyl,and (2) a radical wherein R4 is included in a cyclic system selectedfrom among the piperidine and morpholine groups.

2. The compound 1-phenyl-5-diethylaminomethyl tetrazole.

3. The compound l-alpha-naphthyl 5 di ethylaminomethyl tetrazole.

4. The compound 1 b naphthyl-5-diethylaminomethyl tetrazole.

EDWARD K. HARVILL. ROBERT M. HERBST.

No references cited.

